The present invention relates to compositions, articles of manufacture, extracts, compounds, methods of use, methods of treatment, methods of preparation, etc., which relate to plants of the genus Rhodiola, preferably Rhodiola crenulata, which have a variety of useful and beneficial effects, including, e.g., to enhance blood oxygen and nutrients levels, e.g., through enhancing oxygen transport, to enhance working capacity and endurance, to reduce muscle fatigue, to enhance memory and concentration, to reduce stress, to enhance cardiac and cardiovascular function, to provide antioxidant effects, to protect against oxidation, to provide anti-cancer effects, to promote DNA repair, to provide anti-radiation effects, to protect against radiation, to reduce inflammation, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, preferably, to modulate testosterone levels, and to modulate sleep, especially to promote sleep, to modulate blood lipids, preferably, e.g., to lower cholesterol levels, to promote weight loss, and to enhance sexuability, such as improve sexual performance.
Rhodiola crenulata is a species of Rhodiola which grows mostly in Tibet and south west of China on the altitude between 3400 meters to 5600 meters. It has been used in Tibetan medicine for more than 1000 years for uses that have been limited to curing lung inflammation and cough, for stopping and activating blood, and for treating external wounds and burns. It has been discovered herein that Rhodiola crenulata has other beneficial properties that make it useful for a variety of conditions and diseases, as mentioned above and below.
Rhodiola is a diverse genus of plants which includes more than 50 different species, including, e.g., algida, arctica, crenulata, elongata, gelida, imbricataishidae, iremelica, kirilowii, linearifolia, phariensis, pinnatifida, quadrifida, aff. quadrifida, rosea, sachalinensis, and wolongensis. These species vary from each other widely, differing in, e.g., chromosome number (e.g., Makoto et al., Journal of Japanese Botany, 70(6):334-338, 1995), chemical composition, morphology, medicinal properties, developmental stages (e.g., Ishmuratatova and Satsyperova, Rastitel""nye Resursy., 34(1):3-11, 1998), geographical distribution, etc. Scientific studies (e.g. Peng et al, Chinese Herb Medicine (1995), 26(4): 177-179, and Wang et al, Acta Phrmaceutica Sinica(1992), 27(2): 117-120) indicate constituents of Rhodiola crenulata include, e.g., salidroside, tyrosol, xcex2-sitosterol, gallic acid, pyrogallol, crentulatin, rhodionin, rhodiosin, among which, crenulatin, e.g., is found only in R. crenulata and has not been found in any other Rhodiola species. Rhodiosin and rhodionin exists in some, but not all, Rhodiola species.
The term xe2x80x9cplantxe2x80x9d as used herein refers to seeds, leaves, stems, flowers, roots, berries, bark, or any other plant parts that are useful for the purposes described. For certain uses, it is preferred that the underground portion of the plant, such as the root and rhizoma, be utilized. The leaves, stems, seeds, flowers, berries, bark, or other plant parts, also have medicinal effects and can be used for preparing tea and other beverages, cream, and in food preparation.
Rhodiola of the present invention can be in any form which is effective, including, but not limited to dry powders, grounds, emulsions, extracts, and other conventional compositions. To extract or concentrate the effective ingredients of Rhodiola, typically the plant part is contacted with a suitable solvent, such as water, alcohol, methanol, or any other solvents, or mixed solvents. The choice of the solvent can be made routinely, e.g., based on the properties of the active ingredient that is to be extracted or concentrated by the solvent. Preferred active ingredients of Rhodiola crenulata include, but are not limited to, salidroside, tyrosol, xcex2-sitosterol, gallic acid, pyrogallol, crenulatin, rhodionin, and/or rhodiosin. These ingredients can be extracted in the same step, e.g., using an alcoholic solvent, or they may be extracted individually, each time using a solvent which is especially effective for extracting the particular target ingredient from the plant. In certain embodiments, extraction can be performed by the following process: Milling the selected part, preferably root, to powder. The powder can be soaked in a desired solvent for an amount of time effective to extract the active agents from the Rhodiola. The solution can be filtered and concentrated to produce a paste that contains a high concentration of the constituents extracted by the solvent. In some cases, the paste can be dried to produce a powder extract of Rhodiola crenulata. The content of active ingredient in the extract can be measured using HPLC, UV and other spectrometry methods.
A Rhodiola of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. It can be administered alone, or in combination with any ingredient(s), active or inactive, including in a medicinal form, or as a food or beverage additive.
In preferred embodiments of the invention, Rhodiola is administered orally in any suitable form, including, e.g., whole plant, powdered or pulverized plant material, extract, pill, capsule, granule, tablet or a suspension.
Rhodiola can be combined with any pharmaceutically acceptable carrier. By the phrase, xe2x80x9cpharmaceutically acceptable carriers,xe2x80x9d it is meant any pharmaceutical carrier, such as the standard carriers described, e.g., Remington""s Pharmaceutical Science, Eighteenth Edition, Mack Publishing company, 1990. Examples of suitable carriers are well known in the art and can include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solutions, phosphate buffered saline containing Polysorb 80, water, emulsions such as oil/water emulsion and various type of wetting agents. Other carriers may also include sterile solutions, tablets, coated tablets pharmaceutical and capsules. Typically such carriers contain excipients such as such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols. Such carriers can also include flavor and color additives or other ingredients. Compositions comprising such carriers are formulated by well known conventional methods. Generally excipients formulated with Rhodiola are suitable for oral administration and do not deleteriously react with it, or other active components.
Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose and the like. Other additives include, e.g., antioxidants and preservatives, coloring, flavoring and diluting agents, emulsifying and suspending agents, such as acacia, agar, alginic acid, sodium alginate, bentonite, carbomer, carrageenan, carboxymethylcellulose, cellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxppropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, octoxynol 9, oleyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters, stearyl alcohol, tragacanth, xanthan gum, and derivatives thereof, solvents, and miscellaneous ingredients such as microcrystalline cellulose, citric acid, dextrin, dextrose, liquid glucose, lactic acid, lactose, magnesium chloride, potassium metaphosphate, starch, and the like.
Rhodiola can also be formulated with other active ingredients, such as anti-oxidants, vitamins (A, C, ascorbic acid, B""s, such as B1, thiamine, B6, pyridoxine, B complex, biotin, choline, nicotinic acid, pantothenic acid, B12, cyanocobalamin, and/or B2, D, D2, D3, calciferol, E, such as tocopherol, riboflavin, K, K1, K2). Preferred compounds, include, e.g creatine monohydrate, pyruvate, L-Carnitine, xcex1-lipoic acid, Phytin or Phytic acid, Co Enzyme Q10, NADH, NAD, D-ribose, amino acids such as L-Glutamine, Lysine, chrysin; pre-hormones such as 4-drostenedione, 5-androstenedione, 4(or 5-)androstenediol, 19-nor-4 (or 5-)-drostenedione, 19-nor-4 (or 5-)-androstenediol, Beta-ecdysterone, and 5-Methyl-7-Methoxy Isoflavone. Preferred active ingredients include, e.g., pine pollen, fructus lycii, hippophae rhamnoides, Salvia Miltiorrhiza, Ligusticum, Acanthopanax, Astragalus, Ephedra, codonopsis, polygola tenuifolia Willd, Lilium, Sparganium, ginseng, panax notogiseng, Garcinia, Guggle, Grape Seed Extract or powder, and/or Ginkgo Biloba.
Other plants and herbs which can be formulated with a Rhodiola of the present invention includes those mentioned in various text and publications, e.g., ES Ayensu, Medicinal Plants of West Africa, Reference Publications, Algonac, Mich. (1978); P. Back, The Illustrated Herbal 1987, Hamlyn Publishers, distributed by Octopus Books, Printed in Hong Kong by Mandarin, ISBN 0-600 553 361; F. Bianchini and F. Corbetta, The Fruits of the Earth, translated from Italian by A. Mancinelli, Bloomsbury Books, London, ISBN 1-870630-10-6; H. M. Burkill, The Useful plants of West Tropical Africa, Ed. 2, V. I, Royal Botanic Gardens Kew, ISBN 0-947643-01-X (1985); L. Boulos, Medicinal Plants of North Africa, Reference Publications Inc., Algonac, Mich. (1983); and N. C. Shah, Herbal Folk Medicines in Northern India, J. Ethnopharm, 6:294-295 (1982).
Other active agents include, e.g., antioxidants, anti-carcinogens, anti-inflammatory agents, hormones and hormone antagonists, antibiotics (e.g., amoxicillin) and other bacterial agents, and other medically useful drugs such as those identified in, e.g., Remington""s Pharmaceutical Sciences, Eighteenth Edition, Mack Publishing Company, 1990. A preferred composition of the present invention comprises, about 1%-100%, preferably about 20-70% Rhodiola crenulata extract, more preferably about 60%, said extract having about 0.5-10% salidroside content; 10-45% 5:1 extracted fructus lycii powder (5 kilograms of the herb is used to produce 1 kg of herb powder); 1-20% of hippophae rhamnoides powder; and, optionally, a pharmaceutically-acceptable excipient.
The present invention relates to methods of administering Rhodiola, especially Rhodiola crenulata, e.g., to enhance blood oxygen levels, to enhance working capacity and endurance, to reduce muscle fatigue, to enhance memory and concentration, to reduce stress, to enhance cardiac and cardiovascular function, to improve sexual ability, to provide antioxidant effects, to protect against oxidation, to provide anti-cancer effects, to promote DNA repair, to provide anti-radiation effects, to protect against radiation, to reduce inflammation, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, preferably, to modulate testosterone levels, to increase male virality, to modulate sleep, especially to promote sleep. to modulate blood lipids, preferably, e.g., to lower cholesterol levels, to promote weight loss, to increase estradiol levels, etc., and other conditions and diseases as mentioned above and below.
By the term xe2x80x9cadministering,xe2x80x9d it is meant that Rhodiola is delivered to the host in such a manner that it can achieve the desired purpose. As mentioned Rhodiola can be administered by an effective route, such as orally, topically, rectally, etc. Rhodiola can be administered to any host in need of treatment, e.g., vertebrates, such as mammals, including humans, male humans, female humans, primates, pets, such as cats and dogs, livestock, such as cows, horses, birds, chickens, etc.
An effective amount of Rhodiola is administered to such a host. Effective amounts are such amounts which are useful to achieve the desired effect, preferably a beneficial or therapeutic effect as described above. Such amount can be determined routinely, e.g., by performing a dose-response experiment in which varying doses are administered to cells, tissues, animal models (such as rats or mice in maze-testing, swimming tests, toxicity tests, memory tests as performed by standard psychological testing, etc.) to determine an effective amount in achieving an effect. Amounts are selected based on various factors, including the milieu to which the virus is administered (e.g., a patient with cancer, animal model, tissue culture cells, etc.), the site of the cells to be treated, the age, health, gender, and weight of a patient or animal to be treated, etc. Useful amounts include, 10 milligrams-100 grams, preferably, e.g., 100 milligrams-10 grams, 250 milligrams-2.5 grams, 1 gm, 2 gm, 3 gm, 500 milligrams-1.25 grams. etc., per dosage of different forms of Rhodiola crenulata such as the herbal powder, herbal extract paste or powder, tea and beverages prepared to contain the effective ingredients of Rhodiola, injections, depending upon the need of the recipients and the method of preparation.
In preferred embodiments, the present invention relates to a method of increasing testosterone levels in a host in need thereof, comprising, administering an effective amount of a Rhodiola to said host. Testosterone, principal male hormone, or androgen, is produced mainly in the Leydig cells in the male testes. The Leydig cells also produce two other androgens of less potency and in much smaller quantities. Testosterone stimulates the development of the male secondary sex characteristics after puberty, causing growth of the beard and pubic hair, development of the penis, and change of voice. The hormone also aids in growth, muscular development, and masculine body contour of the adult male.
Testosterone is considered to be a male virilizing hormone. Its effects include maintenance of muscle and bone mass, improving and/or enhancing sexual function and psychological well being among others. As males grow older, especially after the age of 35, a slow decline in testosterone levels is observed which is accompanied by symptoms that have been associated with the condition known as xe2x80x9candropausexe2x80x9d. Symptoms of andropause include lethargy, depression, lack of sexual desire and function, and loss of muscle mass and strength. Increasing testosterone levels therefore can be useful to treat any of the mentioned conditions. Additionally, increasing testosterone levels can be useful in treating certain types of breast cancer in women.
Testosterone levels refer to the amounts of testosterone which are circulating in the blood, e.g., as measured using enzyme-linked immunosorbent assay, HPLC, or any other suitable detection method.
Any effective amount of Rhodiola crenulata can be administered. In accordance with present invention, it has been demonstrated that intake of a standardized Rhodiola crenulata extract (e.g., having 0.1-10%. Preferably 1-6%) salidroside by total weight of composition) produced a significant increase in total testosterone as compared to placebo. For example, after taking 2 grams of standardized rhodiola extract with 2% salidroside, once a day for a month, subjects showed about a 76% increase in total testosterone in the blood as compared to the 6.0% increase in total testosterone level after taking placebo for a month. These amounts, however, can be increased by any value, e.g., at least about 5%, 10%, 15%, 20%, 50%, 60% 70%, 75%, 100%, 2-fold, 5-fold, etc., over amounts which are present in the blood prior to administration.
The present invention also relates to a method of increasing estradiol levels in a host in need thereof, comprising, administering an effective amount of a Rhodiola to said host.
Estradiol is a female sex hormone that stimulates the appearance of secondary female sex characteristics in girls at puberty. Estradiol controls growth of the lining of the uterus during the first part of the menstrual cycle, cause changes in the breast during pregnancy, and regulate various metabolic processes. Increasing estradiol can treat various conditions, including menopausal symptoms, estrogen deficiencies in women (most commonly after menopause; low eight; etc) and inflammation of the vagina. It can also stimulate lactation following childbirth and in the treatment, but not cure, advanced and even disseminated cancer of the prostate gland in men. Amounts of estradiol can be increased by any value, e.g., 5%, 6%, 8%, 10%, 15%, 20%, 30%, 50%, 75%, 100%, 2-fold, 5-fold, etc., over amounts which are present in the blood prior to administration. For example, in Example 10, Rhodiola as effective in increasing estradiol levels by about 12% as compared to only 3% in controls. Thus, Rhodiola can used to treat conditions associated with estrogen deficiency, such as menopuse, perimenopause, low-weight, etc.
Rhodiola can be combined with any agent which raises testosterone and/or estradiol levels. For example, testosterone precursors, such as those disclosed in U.S. Pat. Nos. 5,880,117 and 6,011,027, e.g., 4-androstenediol and 19-nor-4-androstenediol, can be utilized in combination with Rhodiola as a means of increasing testosterone levels in human. Currently, 4-androstenedione, 5-androstenedione, 4-androstenediol, 5-androstenediol, 19-nor-4-androstenedione, 19-nor-5-androstenedione, 19-nor-4-androstenediol, and 19-nor-5-androstenediol, Beta-ecdysterone, and 5-Methyl-7-Methoxy Isoflavone are being used to increase the testosterone level in humans. Rhodiola crenulata can be used with these ingredients to enhance their effects of boosting the testosterone level, other hormones, such as estradiol. Rhodiola crenulata can also be formulated to boost hormonal levels with other herbs, such as wild yam, Epimedium (including all Epimedium species), Angelica, Lycium, panex ginseng, Ganoderma lucidum, Codonopsis, Eleutherococcus, Schisandra chinensis, Atractylodes, and Ligustrum lucidum. 
The present invention also relates methods of improving sleep in a host in need thereof, comprising administering an effective amount of a Rhodiola to said host. By the phrase xe2x80x9cimproving sleep,xe2x80x9d it meant bringing about a beneficial effect on sleep, including, e.g., prolonging sleep time (e.g., as measured in animal models by administering Rhodiola in the presence or absence of a barbiturate, or other sleep-promoting agent, and determining the sleep-prolongation time produced by Rhodiola), increasing time spent in REM-sleep, reducing sleep apnea and other sleep disorders, decreasing insomnia, decreasing amount of time to fall asleep, etc.
Rhodiola can also be formulated with other agents which promote sleep, such as Valerian, Melatonin, Kava Kava, St. John""s Wort, Tryptophan and 5-Hydroxytryptophan, Astragalus, Hops, Passionflower, Skullcap, Chamomile, He Shou Wu, Ashwaganda, and Lady""s Slipper.
The present invention also relates to methods of treating impotence, comprising administering an effective amount of Rhodiola, preferable Rhodiola crenulata. Impotency, or erectile dysfunction, is the inability to achieve an erection. The ability of Rhodiola crenulata to increase the blood oxygen transportation and testosterone level can enhance male sexual ability and performance in some cases. The Rhodiola can be administered immediately prior to performance, or more preferably, on a daily basis according to the regime mentioned above to increase testosterone levels. Rhodiola can also be administered in combination with agents which are used for treating impotency, including, e.g., vasodilators, phosphodiesterase inhibitors, stimulators of NO release, alpha-adrenergic agents, etc.
Administration of Rhodiola crenulata can also be used to enhance blood oxygen levels and transport to body tissues; to enhance working capacity and endurance. By xe2x80x9cworking capacity and endurance,xe2x80x9d it preferably meant that the effective amount increases the ability to perform a physical task, such as in exercise, physical labor, or sports activity, even before fatigue would normally occur; thus, enhanced working capacity and endurance is defined herein not to mean xe2x80x9cfatigue,xe2x80x9d which simply indicates that the performer does not tire. Associated with enhanced working capacity and endurance can be an increase in muscle ATP levels and a reduction in circulating lactic acid levels (see, Examples 2 and 3). Thus, the present invention also relates to methods of increasing muscle ATP levels and/or reducing lactic acid in blood, thereby enhancing working capacity and endurance, improving sexual performance, etc.
As shown in the Example 2, Rhodiola crenulata reduces blood lactic acid (lactate) levels. Such reduction in lactic acid levels indicates that muscle fatigue is reduced. By xe2x80x9cmuscle fatigue,xe2x80x9d it is meant that the muscle cells carry out anaerobic respiration because of lack of oxygen. Reducing muscle fatigue therefore means, e.g., that fewer muscle cells become anaerobic. The present invention therefore also relates to a method of reducing muscle fatigue comprising administering an effective amount of Rhodiola crenulata. Lactic acid can be reduced by an effective amount in ameliorating fatigue, such as at least 10%, 15%, 20%, 25%, 30%, 35%, etc.
As shown in Example 3, Rhodiola crenulata increases the ATP available to muscle, e.g., by increasing aerobic respiration, by increasing oxygen transport, etc. Amounts of ATP can be increased by an effective amount in reducing muscle fatigue, such as 20%, 25%, 30%, 35%, 37%, 40%, 40%, 45%, 50%, etc.
Rhodiola can also be used to enhance or improved memory and concentration (such improved functions are to be distinguished from the more general brain stimulation which indicates increased non-selective neuronal activity, whereas the mentioned improved functions are selective, e.g., by stimulating specific parts of the brain or other organs, or by stimulating specific neural and hormonal systems); to reduce stress, e.g., lower blood pressure, reduce anxiety, promote calmness; to enhance cardiac and cardiovascular function (including, e.g., to protect against heart disease); to provide antioxidant effects and protect against oxidation; to provide anti-cancer effects, e.g., promote cessation of cell growth; to promote DNA repair; to provide anti-radiation effects and to protect against radiation, e.g., as a sun-screen when applied topically to the skin; to reduce inflammation, e.g., systemic inflammation, skin inflammation (where Rhodiola can be administered topically), but with the proviso that it is not lung-inflammation, coughing, or bleeding associated with lung-inflammation and coughing, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, to enhance sexual ability. Rhodiola crenulata in accordance with the present invention is preferably not used to treat external wounds, external burns, lung inflammation, and coughing.